Abstract
The zoonosis caused by Nocardia is increasing seriously. But commonly used antibiotic drugs often lead to resistance. N. seriolae dUTPase (NsdUTPase) plays a key role in the proliferation of Nocardia, and was regarded as a potent drug target. However, there was little report about the NsdUTPase inhibitors. In this study, we discovered a series of novel NsdUTPase inhibitors to fight against Nocardia. The first crystal structure of NsdUTPase was released, and a structure-based computational design was performed. Compounds 4b and 12b exhibited promising activities towards NsdUTPase (IC50 = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti-Nocardia activity (MIC value ranges from 0.5 to 2 mg/L) and low cytotoxicity, which were better than approved drugs oxytetracycline and florfenicol. Molecular modelling study indicated that hydrophobic interaction might be the main contribution for ligand binding. Our results suggested that NsdUTPase inhibitors might be a useful way to repress Nocardia.
Keywords:
Computer-aided drug design; Nocardia; antibiotics; dUTPase.
MeSH terms
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Anti-Bacterial Agents* / chemical synthesis
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Anti-Bacterial Agents* / chemistry
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Anti-Bacterial Agents* / pharmacology
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Dose-Response Relationship, Drug*
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Drug Design
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Drug Discovery
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Enzyme Inhibitors* / chemical synthesis
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacology
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Humans
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Microbial Sensitivity Tests*
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Models, Molecular
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Molecular Structure
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Nocardia* / enzymology
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Pyrophosphatases* / antagonists & inhibitors
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Pyrophosphatases* / metabolism
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Structure-Activity Relationship
Substances
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dUTP pyrophosphatase
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Pyrophosphatases
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Enzyme Inhibitors
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Anti-Bacterial Agents
Grants and funding
This work is supported by the National Natural Science Foundation of China (Nos. 32402442 and 31402036), the Postdoctoral Fellowship Program of CPSF (No. GZB20230198), the Hubei Provincial Natural Science Foundation of China (2024AFB465) and the Wuhan Huanghe Talents Plan. We also thank the experimental facility and the technical services provided by the National Synchrotron Radiation Research Center (NSRRC), a national user facility supported by the Ministry of Science and Technology (MOST), Taiwan, ROC.